The cerebellum is a region of brain positioned below cerebral cortex. It is approximately 10% of the brain by volume, but its main cells, namely granule neurons, are more numerous than all of the neurons in the rest of the brain combined. The cerebellum has a primary role in motor control and learning, but appears to participate in higher cognitive functions like attention and language, as well as in emotions such as fear and pleasure. A prevailing hypothesis states that the cerebellum is, in principle, a sensory structure. In motor-related activity, it adjusts and fine-tunes motor activities in response to sensory inputs. Likewise, the cerebellum may also play an important role in coordinating cognitive tasks. Although the cerebellum contribution to mental disease and cognitive function has been shown, this important structure of the brain has never been utilized as a target for therapeutic agents.
The α6β2/3δ receptors are subtypes of the GABAA receptor family abundantly and exclusively expressed within the granule neurons of the cerebellum; the most abundant neurons within the CNS. GABAA receptors are the main target of most anesthetics, but there was little evidence that phencyclidine (PCP) or ketamine affect these receptors. We have shown that at clinically relevant concentrations, in vitro and in situ, ketamine, but not PCP, selectively modulates α6β2δ and α6β3δ GABAA receptors. These data suggest that the selection of ketamine from among 200 different PCP different analogues for clinical use may be due to its selective actions on α6β2/3δ receptors within the cerebellum. Given the abundance of the granule neurons, even a minute increase in the activity of α6β2/3δ GABAA receptors by ketamine can potentially impact the excitability of the granule neurons and thus transmission of information through the cerebellum. However, ketamine has side effects such as vivid dreams, illusions, disruptions of cognitive function, mood changes. Thus, alternatives to ketamine are desired.